Unit 13
Unit 13
Unit 13
The activation of B lymphocytes is different for the various types of existing B lymphocytes. Remember that
there are three types of virgin B lymphocytes, B lymphocytes 2F (follicular), B 1 and B 2ZM (marginal zone
of the spleen):
- 2F B lymphocytes: they are the most abundant. They have very diverse B-cell receptors (BCRs). They are
located in the follicles of the ganglia, spleen and mucosa-associated lymphoid tissues (MALT). As 2F B
lymphocytes account for 90% of all B lymphocytes, when we talk about B lymphocytes generically, we
refer to them.
- B lymphocytes 1 and B 2ZM : are rare. They have little diverse BCR. B 1 lymphocytes are found in the
pleural, peritoneal and pericardial cavities and 2ZM B lymphocytes in the marginal zone of the spleen.
The activation of B lymphocytes is carried out in two phases that serve a series of objectives. The first phase
is common to all types of B lymphocytes, while the second is specific to 2F B lymphocytes: in the first phase
of activation, B lymphocytes perform clonal expansion, antibody secretion and differentiation to plasma
cells. In the second phase, memory B lymphocytes are generated. The 2F B lymphocytes are the only ones
that reach the second phase and, therefore, only they generate memory B lymphocytes.
Exposed in detail, the activation of 2F B lymphocytes develops as follows:
The details of B1 and B 2ZM cell activation will be described at the end of the chapter.
- The dark zone. It contains abundant B lymphocytes and some HF T. B lymphocytes are continuously
proliferating with the help of HF T lymphocytes.
- The clear zone: contains B lymphocytes and follicular dendritic cells.
Second phase of activation of 2F B lymphocytes.
(a) Some activated B lymphocytes (LB) in the
extrafollicular region return to the follicle. (b)
They form the germinal center, where clonal
expansion continues. (c) In the germinal center,
LBs mature with the collaboration of HF T
lymphocytes (LT HF) and follicular dendritic cells
(DC F). (d) After maturing, LBs differentiate into
memory LBs (LB M) and long-lived plasma cells.
(e) Both LB M and plasma cells leave the ganglion
and secrete antibodies (Ac).
The formation of the germinal center manifests clinically with inflammation of the lymph nodes. To get to
this point there have previously been several clonal expansion events. First, the expansion of specific T
lymphocytes against the antigen (T H1, T H17 or T H2). Second, the expansion of HF T lymphocytes. Thirdly,
the expansion of B lymphocytes in their first phase. Finally, clonal expansion of B lymphocytes takes place
in the germinal center. Swollen nodes may become apparent on clinical examination.
B lymphocytes remature in the germinal center and do so simultaneously with clonal expansion. Remember
that the maturation of B lymphocytes happens mostly in the bone marrow, to give rise to virgin B
lymphocytes. After the recognition of the antigen, its activation and the formation of the germinal center,
the B lymphocytes undergo a new maturation process. This process aims for B lymphocytes to mature
against the pathogen they are attacking. Maturation consists of gene recombinations that promote isotype
change and affinity maturation.
The isotype change consists of a change of the constant region of the BCR heavy chain (regions C H1-3 ) so
that the IgM isotype of the BCR becomes IgG, IgE or IgA. In addition, secreted antibodies also change their
constant regions. The antibody isotype chosen depends on the cytokines present in the ganglion. These
cytokines are those secreted by the profile of T lymphocytes that have expanded in the ganglion against the
same pathogen. Specifically:
- If it is an H1-type response to extracellular bacteria, H1 T cells secrete the cytokine IFN-γ (interferon-γ).
This cytokine is present in abundance in the ganglion and reaches the B lymphocytes of the germinal
center to induce the change of isotype to IgG. As we will explain in Chapter 14, IgG is the most effective
antibody against these pathogens.
- If it is a T-type H2 response to a helminth, H2 T cells secrete the cytokine IL-4. This cytokine, present
mostly in the ganglion, reaches the B lymphocytes of the germinal center and induces the change of
isotype to IgE.
- In the mucous membranes, the presence of REG T lymphocytes (regulatory T) makes the majority
cytokine TGF-β (tissue growth factor β). This cytokine reaches the B lymphocytes and induces the
change of isotype to IgA, compared to commensals of the mucous membranes.
The molecular mechanism that explains the isotype change is gene recombination. The BCR heavy chain
gene contains the exons of the constant regions ordered as follows: constant of M (Cμ), constant of G (Cγ),
constant of E (Cɛ) and constant of A (Cα). During recombinations, a loop is formed that forces the approach
of the exon Cμ to one of the exons Cγ, Cɛ or Cα. The size of the loop to favor one or the other approach
depends on the cytokines present in the germinal center.
- If the change is from IgM to IgG, the cytokines present induce the recombination of the Cμ regions with
Cγ in order to express the Cγ region.
- If the change is from IgM to IgE, the cytokines present induce the recombination of the regions of Cμ
with Cɛ in order to express the Cɛ region.
- If the change is from IgM to IgA, the cytokines present induce the recombination of the regions of Cμ
with Cα in order to express the Cα region.
Affinity maturation consists of converting the variable regions of the BCR light chain into regions of higher
affinity towards the pathogen antigen. This process happens in two parts:
- Somatic hypermutation: consists of a series of mutations on the variable region of the BCR, allowed in
the dark zone of the germinal center.
- Selection of high-affinity B lymphocytes: through selection, dendritic cells interact with high-affinity B
lymphocytes and promote their survival. This selection is carried out by special dendritic cells called
follicular dendritic cells, located in the clear area of the germinal center. Dendritic cells retain the
antigen on their surface by phagocytic receptors and show it to B lymphocytes. B lymphocytes have two
fates:
o B cells with hypermutated BCR that bind to dendritic cells survive.
o B cells with hypermutated BCR that do not bind to dendritic cells die.
At the end of the immune response, when there is little antigen left, it is retained on the surface of
dendritic cells and B lymphocytes must compete to bind to the antigen. In this situation, only B
lymphocytes with higher affinity BCRs survive.
The binding of these antigens to the BCR of B 1 and B 2ZM lymphocytes induces their activation. This is
because the multivalent binding to several BCR molecules of the same B cell is strong enough to induce B
cell activation. This type of B cell activation does not always require warning from the innate immune
system. In addition, remember that B 1 lymphocytes and 2ZM B lymphocytes have not very diverse
receptors that only recognize frequent antigens. Their low diversity together with their independence from
the innate immune system makes these B lymphocytes considered similar to cells of the innate immune
system.
The activation of B 1 lymphocytes and 2ZM B lymphocytes triggers the following processes:
1. Clonal expansion.
2. Secretion of low-affinity IgM antibodies.
3. Formation of short-lived plasma cells.
Its function, therefore, is immunological but also homeostatic, that is, to maintain the proper functioning of
the organism. In particular, natural antibodies against erythrocytes are very important in blood transfusions
or organ transplants.